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Cancer and Skin Lesions / Genetic and Rare Skin Diseases. · Journal article
American Journal of Physiology-cell Physiology · August 17, 2026
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This is an in vitro mechanistic study establishing a CRISPR-edited keratinocyte model of Hailey Hailey Disease and identifying an insulin-activated PI3K-AKT-Rac1 pathway required for actin dynamics and cell spreading that is defective in SPCA1 mutants. Small molecule and transgenic rescue restored phenotypes in culture, providing a putative target for therapy but requiring in vivo validation and clinical testing.
In vitro cell model study with CRISPR/Cas9 gene editing and mechanistic characterization. Immortalized human hTERT keratinocytes, wild-type and CRISPR-edited for ATP2C1 (heterozygous and homozygous null mutants). Intervention: CRISPR/Cas9-mediated ATP2C1 knockout (single and bi-allelic); hSPCA1 transgenic expression; CDN1163 (small molecule Ca2+-ATPase agonist) treatment. Compared with: Wild-type immortalized human hTERT keratinocytes.
Both heterozygous and homozygous ATP2C1 null mutants showed near complete loss of desmosomal and adherens junction cadherins despite proportionate SPCA1 expression loss SPCA1 is required for dynamic reorganization of actin cytoskeleton in keratinocyte spreading PI3K-AKT-Rac1 signaling pathway is insulin-activated and required for lamellipodia formation, defective in SPCA1 mutants
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This work provides a mechanistic framework and cell model for understanding HHD pathogenesis and testing therapeutic candidates; however, the findings remain restricted to cultured cells and require animal and clinical validation before informing patient treatment.
In vitro mechanistic study in immortalized keratinocytes using CRISPR knockouts, demonstrating pathway defects and proof-of-concept rescue; lacks in vivo validation or clinical outcome data required for stronger evidence.
As stated by the source record.
This work provides a mechanistic framework and cell model for understanding HHD pathogenesis and testing therapeutic candidates; however, the findings remain restricted to cultured cells and require animal and clinical validation before informing patient treatment.
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Abstract Hailey Hailey Disease (HHD) is an autosomal dominant cutaneous disorder caused by mutations in ATP2C1, the gene encoding the Golgi/secretory pathway Ca 2+ -ATPase SPCA1. Characterized by suprabasal acantholysis and intertriginous blistering of the skin, HHD treatment focuses on managing symptoms as there is no cure. Challenges to targeted therapy are due to the lack of facile and reliable models, both human and rodent, for mechanistic studies. Here we validate and characterize CRISPR/Cas9 mediated single and bi-allelic ATP2C1 knockouts in immortalized human hTERT keratinocytes. Whereas SPCA1 expression, Golgi morphology and Golgi Ca 2+ accumulation were proportionately affected in heterozygous and homozygous ATP2C1 null mutants as expected, both single and double allelic mutants showed near complete loss of cadherins associated with desmosomal and adherens junctions. HHD is characterized by poor wound healing and impaired keratinocyte migration. We show that SPCA1 is required for dynamic reorganization of actin cytoskeleton in keratinocyte spreading. We identified an insulin activated PI3K-AKT-Rac1 signaling pathway required for lamellipodia formation and keratinocyte spreading, defective in SPCA1 mutants. Transgenic expression of hSPCA1 or treatment with CDN1163, a small molecule Ca 2+ -ATPase agonist, restored defective phenotypes in the HHD model, paving the way for future therapeutic approaches to treat this disorder.
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